Treatment of psychosis with meta-sulfonamido-benzamide derivatives

ABSTRACT

Meta-sulfonamido-benzamide derivatives of the formula: ##STR1## [wherein R is a hydrogen atom or a lower alkyl, cyano, or lower alkanesulfonyl group; 
     R 1  is a lower alkyl, phenyl, amino, lower alkylamino, di(lower)alkylamino, or C 4  -C 5  alkyleneamino group; 
     R 2  is a hydrogen or halogen atom or a lower alkyl, di(lower)alkylamino, or lower alkoxy group; 
     R 3  is a hydrogen atom or a methyl or methoxy group; 
     R 4  is a hydrogen or halogen atom; 
     R 5  is a lower alkyl, lower alkenyl, C 3  -C 6  cycloalkyl, benzyl, or halogenobenzyl group; and n is 1 or zero] 
     or their acid addition salts, showing pharmacological activity such as anti-emetic or psychotropic activity, are provided via several routes.

This application is a division of Ser. No. 124,726, filed Feb. 26, 1980,now U.S. Pat. No. 4,350,635 which is a division of Ser. No. 872,584,filed Jan. 26, 1978, now abandoned.

The present invention relates to meta-sulfonamido-benzamide derivativesand a process for the production thereof.

The meta-sulfonamido-benzamide derivatives provided by the presentinvention are compounds of the formula: ##STR2## [wherein R is ahydrogen atom or a lower alkyl, cyano, or lower alkanesulfonyl group;

R¹ is a lower alkyl, phenyl, amino, lower alkylamino,di(lower)alkylamino, or C₄ -C₅ alkyleneamino group;

R² is a hydrogen or halogen atom or a lower alkyl, di(lower)alkylamino,or lower alkoxy group;

R³ is a hydrogen atom or a methyl or methoxy group;

R⁴ is a hydrogen or halogen atom;

R⁵ is a lower alkyl, lower alkenyl, C₃ -C₆ cycloalkyl, benzyl, orhalogenobenzyl group; and n is 1 or zero]

and their acid addition salts.

As used in this specification, the term "lower alkyl" means a straightchain or branched-chain alkyl group which preferably contains from 1 to6 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl,pentyl, hexyl and the like). The methyl group is preferred, except thatthe ethyl group is the preferred lower alkyl group for R⁵. The term"lower alkoxy group" means a straight or branched alkoxy group whichpreferably contains from 1 to 6 carbon atoms (e.g. methoxy, ethoxy,propoxy, isopropoxy, butoxy, pentoxy group). The methoxy group is thepreferred lower alkoxy group. The term "lower alkanesulfonyl" means astraight or branched alkanesulfonyl group preferably containing from 1to 6 carbon atoms (e.g., methanesulfonyl, ethanesulfonyl,propanesulfonyl, butanesulfonyl, pentanesulfonyl, and the like). Themethanesulfonyl group is the preferred lower alkanesulfonyl group. Theterm "lower-alkylamino" means a straight or branched alkylamino group of1 to 6 carbon atoms (e.g. methylamino, ethylamino, propylamino,isopropylamino, butylamino, pentylamino, and the like), and themethylamino group is preferred. The term "di(lower)alkylamino" means aC₂ -C₁₂ dialkylamino group in which the two alkyl groups are the same ordifferent (e.g. dimethylamino, diethylamino, methylethylamino,ethylpropylamino, methylbutylamino, dibutylamino, dihexylamino, and thelike). The dimethylamino group is preferred. The term "lower alkenyl"means a straight or branched alkenyl group preferably containing from 2to 6 carbon atoms (e.g. vinyl, allyl, butenyl, pentenyl, and the like).The term "halogen" means fluorine, chlorine, bromine, or iodine. Thepreferred halogen for R² is chlorine or fluorine. The term "C₃ -C₆cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.The cyclohexyl group is the preferred cycloalkyl group. The term "C₄ -C₅alkyleneamino group" means a pyrrolidino or piperidino group, and thepiperidino group is preferred. The term "halogenobenzyl" denoted by R⁵includes an o-halogenobenzyl group such as o-chlorobenzyl oro-fluorobenzyl and a p-halogenobenzyl group such as p-chlorobenzyl orp-fluorobenzyl.

Preferred compounds of formula I hereinbefore are those of the formula:##STR3## [wherein R is a hydrogen atom or a lower alkyl, cyano, or loweralkanesulfonyl group;

R¹ is a lower alkyl, phenyl, amino, lower alkylamino, ordi(lower)alkylamino group;

R² is a hydrogen or halogen atom or a lower alkyl, di(lower)alkylamino,or lower alkoxy group;

R³ is a hydrogen atom or a methyl or methoxy group;

R⁴ is a hydrogen or halogen atom; and

R⁵ is a lower alkyl, lower alkenyl, C₃ -C₆ cycloalkyl, benzyl, orhalogenobenzyl group]

or their acid addition salts.

More preferred compounds of formula Ia hereinbefore are those in whichR, R³, and R⁴ each is a hydrogen atom; R¹ is a lower alkyl, phenyl,amino, methylamino or dimethylamino group; R² is a hydrogen or chlorineatom or a methyl group; and R⁵ is an ethyl or halogenobenzyl group.

Examples of compounds of formula I hereinbefore are:

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-methanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-methanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-benzenesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-(N-cyanomethanesulfonamido)benzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-(N-methylethanesulfonamido)benzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-fluoro-5-methanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-ethanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-propanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-dimethylamino-5-methanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-ethanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-dimethylaminosulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-butanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2,3-dimethoxy-5-methanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2,4-dimethoxy-5-methanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-ethanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-methanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-ethyl-5-methanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-3-methyl-5-ethanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-ethyl-5-ethanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-3-methyl-5-methanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-dimethylaminosulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-6-chloro-5-methanesulfonamidobenzamide,

N-(1-cyclohexyl-3-pyrrolidinylmethyl)-2-methoxy-5-methanesulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-(N-methylmethanesulfonamido)benzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-t-butylaminosulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-aminosulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-t-butylaminosulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-aminosulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-piperidinosulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-5-methylaminosulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-t-butylaminosulfonamidobenzamide,

N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-aminosulfonamidobenzamide,

N-(1-allyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-methanesulfonamidobenzamide,

N-(1-benzyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-methanesulfonamidobenzamide,

N-(1-allyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-methanesulfonamidobenzamide,and

N-(1-p-fluorobenzyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-methanesulfonamidobenzamide.

According to the process provided by the present invention, themeta-sulfonamido-benzamide derivatives (i.e. the compounds of formula Ihereinbefore and their acid addition salts) are manufactured by

a. reacting a dihalogeno compound of the formula: ##STR4## [wherein Xand X¹ each is a halogen atom; and R, R¹, R², R³, R⁴, R⁵, and n each hasthe significance given earlier]

with an amine of the formula:

    --NH.sub.2                                                 III

[wherein R⁵ has the significance given earlier];

b. reacting an anilino compound of the formula: ##STR5## [wherein R, R²,R³, R⁴, R⁵, and n each has the significance given earlier]

with a sulfonating agent of the formula:

    A--SO.sub.2 R.sup.1                                        V

[wherein A is a reactive residue and R¹ has the significance givenearlier[; or

c. reacting a benzoic derivative of the formula: ##STR6## [wherein A¹ isa reactive residue, and R, R¹, R², R³ and R⁴ each has the significancegiven earlier]

with a diamino compound of the formula: ##STR7## [wherein R⁵ and n eachhas the significance given earlier] and, if desired, converting a freebase obtained into an acid addition salt or converting an acid additionsalt obtained into a free base or into a different acid addition salt.

The reaction of a dihalogeno compound of formula II with an amine offormula III can be carried out in the presence or absence of a suitablesolvent (e.g. water, ethanol, methylene chloride, pyridine, ortriethylamine) at a temperature above room temperature (e.g. 15° C. to100° C.). The amine of formula III illustratively includes methylamine,ethylamine, propylamine, butylamine, allylamine, butenylamine,cyclopropylamine, cyclohexylamine, benzylamine, o-chlorobenzylamine, andp-fluorobenzylamine.

The reaction of an anilino compound of formula IV with a sulfonatingagent of formula V can be carried out in accordance with methods knownper se. The sulfonating agent of formula V illustratively includes ahalogenide (e.g. chloride, bromide, iodide), an active ester (e.g.p-nitrophenyl ester, benzyl ester, trityl ester), and an anhydride (e.g.methanesulfonic anhydride, or ethanesulfonic anhydride) of a prescribedsulfonic acid having the moiety of R¹. The sulfonation is carried out inan inert solvent (e.g. methylene chloride, benzene, tetrahydrofuran, ordioxane) in the presence of a base such as an organic base (e.g.triethylamine or pyridine) or an inorganic base (e.g. potassiumcarbonate or sodium hydrogencarbonate) at a temperature below or aboveroom temperature (e.g. temperature in the range of 0° C. to 100° C.).Alternatively, the organic base may be used in the form of the solvent.The reaction can generally result in a high yield. When R is a loweralkyl, cyano, or lower alkanesulfonyl group, only 1 mol equivalent ofthe group --SO₂ R¹ can be introduced under the sulfonation of thisinvention. Still, when R is a hydrogen atom, 2 mol equivalents of thegroup --SO₂ R¹ may be optionally introduced but the second group can beeasily replaced by a hydrogen atom only by treating the resultantproduct with an inorganic base such as aqueous alkali hydroxide (e.g.aqueous sodium hydroxide or potassium hydroxide).

A compound of formula I hereinbefore in which R is a hydrogen atom maybe subjected to alkylation according to methods known per se. Still, acompound of formula I in which R is a lower alkanesulfonyl group and R¹is a di(lower)alkylamino group, if desired, may be treated with aninorganic base such as aqueous alkali hydroxide (e.g. aqueous sodiumhydroxide) for removing the lower alkanesulfonyl group being liable tohydrolysis. Additionally, the product of formula I hereinbefore in whichR¹ is a t-butylamino group may be treated with trifluoroacetic acid forremoval of the tertiary butyl group whereby the compound of formula Ihereinbefore in which R¹ is an amino group is obtained.

The reaction of a benzoic derivative of formula VI with a diaminocompound of formula VII can be carried out in accordance with methodswhich are known per se in peptide chemistry; for example, by the mixedanhydride, azide, ester, or acid chloride method. For example, a benzoicderivative of formula VI in which the reactive residue is in the form ofan ester group (e.g. the lower alkyl, p-nitrophenyl, or2,4-dinitrophenyl ester group) can be condensed with an appropriatecompound of formula VII at ordinary temperature (e.g. 15° C. to 25° C.).In another method, an appropriate benzoic derivative of formula VI inwhich the reactive residue is in the form of an acid chloride can becondensed with a diamino compound of formula VII in the presence of abase such as an organic base (e.g. triethylamine or pyridine) or aninorganic base (e.g. sodium carbonate, potassium hydrogencarbonate, orsodium hydroxide) at ordinary temperature.

The starting materials of formula II hereinbefore can be prepared, forexample, by reacting a tetrahydrofuryl compound of the formula: ##STR8##[wherein, R, R¹, R², R³, R⁴, and n each has the significance givenearlier]

with a halogenating agent (e.g. thionyl chloride) according to methodsknown per se. The halogenation may be carried out in an inert solvent(e.g. chloroform, benzene, acetonitrile, methylene chloride, or carbontetrachloride) at a temperature above room temperature (e.g. ca. 25° C.to ca. 200° C.).

The tetrahydrofuryl compound of formula VIII can be prepared by reactinga compound of the formula: ##STR9## [wherein A² is a reactive residue;and R, R¹, R², R³, and R⁴ each has the significance given earlier]

with a tetrahydrofuran derivative of the formula: ##STR10## [wherein nhas the significance given earlier] in accordance with methods known perse. The condensation can be carried out in an inert solvent (e.g.benzene, toluene, methylene chloride, dimethylformamide, ortetrahydrofuran) at a temperature below or above room temperature (e.g.0° C. to ca. 100° l C.).

The compound of formula IX can be prepared by subjecting a compound ofthe formula: ##STR11## [wherein A³ is a hydroxy group or a reactiveresidue; R², R³, and R⁴ each has the significance given earlier] tonitration, reduction of the nitro group into an amino group,introduction of the group R, and sulfonation given earlier in anappropriate combination.

The starting materials of formula IV hereinbefore can be prepared, forexample, by reducing a nitro compound of the formula: ##STR12## [whereinR², R³, R⁴, R⁵, and n each has the significance given earlier]

by methods known per se for converting a nitro group into an aminogroup; e.g. catalytic hydrogenation over palladium/carbon, platinumoxide, or Raney nickel; tin/hydrochloric acid or iron/hydrochloric acidreduction. If necessary, a resulting anilino compound is subjected tointroduction of the group R by methods known per se. Thus, the loweralkyl group denoted by R can be introduced by monoalkylation of anaromatic primary amine, adopting a lower alkyl iodide or di(lower)alkylsulfate method or a combination of N-acylation and reduction of acarbonyl group.

The lower alkanesulfonyl group denoted by R can be introduced accordingto the method given earlier for introduction of the group --SO₂ R¹. Thecyano group denoted by R can be introduced, for example, by reacting acorresponding anilino compound with ethyl orthoformate and sodium azidein acetic acid and treating the resulting tetrazolyl compound with abase (e.g. aqueous sodium hydroxide) at a temperature above roomtemperature (e.g. ca. 15° C. to ca. 120° C.).

The nitro compound of formula XII can be obtained by nitrating acompound of formula XI by methods known per se and condensing aresulting compound of the formula: ##STR13## [wherein R², R³, R⁴, and A³each has the significance given earlier]

with a diamine of formula VII according to the method given earlier forthe condensation of a benzoic derivative of formula VI with a diamine offormula VII.

The starting materials of formula VI hereinbefore can be prepared, forexample, by reacting a compound of the formula: ##STR14## [wherein R¹,R², R³, R⁴, and A each has the significance given earlier]

with a sulfonating agent of formula V according to the method givenearlier for the condensation of an anilino compound of formula IV with asulfonating agent of formula V. The compound of formula XIV can beprepared by reducing a compound of formula XIII to a correspondinganilino compound and, if desired, introducing the group R into the aminogroup of the anilino compound according to the method given earlier.

The compounds of formula I hereinbefore form acid addition salts withinorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, nitric acid, thiocyanic acid; and the like) andwith organic acids (e.g. acetic acid, oxalic acid, succinic acid, maleicacid, malic acid, phthalic acid, tartaric acid, citric acid,methanesulfonic acid, toluenesulfonic acid, and the like). The acidaddition salts can be prepared in accordance with well known methods;for example, by treating a base of formula I with an appropriate acid.An acid addition salt may be converted into a different acid additionsalt by methods known per se. Of these acid addition salts, thepharmaceutically acceptable acid addition salts are preferable.

The compounds of formula I hereinbefore and their acid addition saltshave anti-emetic and psychotropic activity. Thus, they are useful asanti-peptic-ulcer agents and neuroleptics.

The anti-emetic activity of the meta-sulfonamidobenzamide derivatives inthis invention are shown by administering them orally to male beagledogs of 10 to 20 months age, treating subcutaneously with 0.1 mg/kg ofapomorphine, and examining the number vomiting in 30 minutes. The resultis shown by an ED₅₀ (mg/kg) which means a dose in induce 50% inhibitionof vomiting. [Janssen, P. A. J. et al., Arzneim.-Forsch. 18 (3) 261-279(1968)]

The psychotropic activity can be shown in the antagonism in DS male miceto apomorphine-induced hyperactivity on spontaneous mobilities. Thistest is carried out by administering orally a test compound to the mice,examining an hour later an amount of spontaneous mobilities for 15minutes, administering subcutaneously 2.5 mg/kg of metamphetamine tothem and examining another amount of spontaneous mobilities for 10minutes. The result is shown by an ED₅₀ (mg/kg) which means a dose toinduce 50% inhibition on spontaneous mobilities. [Janssen, P. A. J. etal., ibid.]

The compounds of formula I and their pharmaceutically acceptable acidaddition salts may be used as medicaments; for example, in the form ofpharmaceutical preparations which contain them in combination with acompatible pharmaceutical carrier material. This carrier material can bean organic or inorganic carrier material suitable for enteral orparenteral administration (e.g. water, lactose, gelatin, starches,magnesium stearate, talc, vegetable oils, gums, polyalkyleneglycols,petroleum jelly, etc.). The pharmaceutical preparations can be made upin a solid form (e.g. tablets, dragees, capsules, etc.) or in a liquidform (e.g. solutions, suspensions, or emulsions). Pharmaceuticalpreparations in a form adopted for injection purposes may be subjectedto conventional pharmaceutical operations such as sterilization and/ormay contain conventional pharmaceutical adjuvants such as preservatives,stabilizers, wetting agents, emulsifiers, buffers, etc.

The dosage in which the compounds of formula I and theirpharmaceutically acceptable acid addition salts may be administered canvary depending upon the requirements of the patient and the directionsof the attending physician. A preferred daily dosage for human adults isof the order of about 30 mg to about 350 mg for oral administration.

Benzamide derivatives includingN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide(sulpiride) have been known as an anti-peptic-ulcer agent oranti-depressant.

Presently preferred and practical embodiments of the present inventionare illustratively shown in the following examples.

EXAMPLE 1

(1) A mixture of 2,4-dichlorobenzoic acid (67.4 g), absolute methanol(135 ml), and copper powder (3.37 g) is refluxed for 6-7 hours whileintroducing gaseous dimethylamine. The reaction mixture is mixed with alarge amount of water, acidified with hydrochloric acid, and shaken withether. The organic layer is washed with water, dried over sodiumsulfate, and evaporated to remove the solvent. The residue is washedwith isopropyl ether and filtered to give 2-methoxy-4-chlorobenzoic acid(43.6 g) as crystals melting at 139.5° to 141° C.

(2) Above product (3.25 g) is added dropwise to fuming nitric acid(specific gravity; 1.52) (10 ml) at -30° C. with stirring, and theresultant mixture is stirred for 10 minutes. The reaction mixture ispoured into icy water and shaken with chloroform/methanol. The organiclayer is washed with water, dried over sodium sulfate, and evaporated toremove the solvent. The residue is washed with isopropyl ether andfiltered to give 2-methoxy-4-chloro-5-nitrobenzoic acid (2.85 g) ascrystals melting at 184° to 185° C. (Helv. Chim. Acta., 40, 369 (1957)).

NMR: δ_(ppm) ^(d).sbsp.6^(-DMSO) 4.00 s. 3H, OCH₃ ; 7.48 s. 1H, H₃ ;8.40 s. 1H, H₆ ; 12.3-15 br. 1H, COOH

(3) A mixture of 2-methoxy-4-chloro-5-nitrobenzoic-acid (900 mg) andthionyl chloride (5 ml) is refluxed for 30 minutes, and the resultantmixture is evaporated to remove the thionyl chloride. The residue ismixed with benzene and evaporated to remove the benzene. The residue ismixed with triethtylamine (790 mg) and dry methylene chloride (9 ml),and a solution of 1-ethyl-2-aminomethylpyrrolidine (750 mg) andmethylene chloride (4 ml) is added dropwise thereto with ice cooling andstirring. The resultant mixture is stirred at room temperature for 15minutes. The reaction mixture is mixed with aqueous sodiumhydrogencarbonate and shaken with methylene chloride. The organic layeris washed with water, dried over sodium sulfate, and evaporated toremove the solvent. The residue is mixed with ether and shaken withdilute hydrochloric acid. The aqueous layer is made alkaline withaqueous sodium hydrogencarbonate, and shaken with methylene chloride.The organic layer is washed with water, dried over sodium sulfate, andevaporated to remove the solvent. The residue is recrystallized fromethyl acetate/isopropyl ether to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-nitrobenzamide(679 mg) as crystals melting at 107° to 108° C.

Anal. Cald. for C₁₅ H₂₀ O₄ N₃ Cl: C,52.71; H,5.90; N,12.29; Cl,10.37.Found: C,52.90; H,6.00; N,12.28; Cl,10.63.

(4) Above product (7.33 g) is mixed with a solution of conc.hydrochloric acid (36.7 ml) and water (73.3 ml), and the resultantmixture is heated at 50° C., mixed with tin chips (7.7 g), and stirredat 50° C. for 4 hours. After cooling, the reaction mixture is madealkaline with aqueous sodium hydroxide and shaken with methylenechloride. The organic layer is washed with water, dried over sodiumsulfate, and evaporated to remove the solvent. The residue ischromatographed on a column of alumina, which is eluted with methylenechloride. The eluate is evaporated to remove the solvent. The residue iswashed with isopropyl ether/petroleum ether to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-aminobenzamide(5.38 g). The product is recrystallized from isopropyl ether/petroleumether to give the crystals melting at 85° to 86.5° C.

Anal. Calcd. for C₁₅ H₂₂ O₂ N₃ Cl: C,57.78; H,7.11; N,13.48; Cl,11.37.Found: C,57.63; H,7.18; N,13.55; Cl,11.66.

(5) To a solution of above product (4.1 g) and triethylamine (2.93 g) indry methylene chloride (41 ml), a solution of methanesulfonyl chloride(3.18 g) and dry methylene chloride (8.2 ml) is added dropwise with icecooling. After removing the ice bath, the reaction mixture is stirred atroom temperature for 45 minutes. The reaction mixture is made alkalinewith aqueous sodium hydrogencarbonate and shaken with methylenechloride. The organic layer is washed with water, dried over sodiumsulfate, and evaporated to remove the solvent. The residue is washedwith ethyl acetate/isopropyl ether to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-N,N-bis(methanesulfonyl)aminobenzamide(5.83 g) as crystals melting at 153° to 155° C.

Anal. Calcd. for C₁₇ H₂₆ O₆ N₃ S₂ Cl: C,43.63; H,5.60; N,8.98; S,13.70;Cl,7.58. Found: C,43.37; H,5.73; N,8.98; S,13.79; Cl,7.72.

(6) A suspension of above product (5.75 g) in 10% sodium hydroxide (57.5ml) is stirred with heating at 50° C. for 30 minutes. After the cooling,the reaction mixture is acidified with conc. hydrochloric acid, madealkaline with aqueous sodium hydrogencarbonate, saturated with sodiumchloride, and shaken with methylene chloride. The organic layer iswashed with saturated brine, dried over sodium sulfate, and evaporatedto remove the methylene chloride. The residue is chromatographed on acolumn of alumina, which is eluted with methylene chloride singly andwith 2% methanol/methylene chloride and evaporated to remove thesolvent. The residue is washed with ethyl acetate/isopropyl ether togiveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-methanesulfonamidobenzamide(4.3 g), which is recrystallized from ethyl acetate/isopropyl ether togive colorless prism crystals melting at 126° to 127.5° C.

Anal. Calcd. for C₁₆ H₂₄ O₄ N₃ SCl: C,49.29; H,6.20; N,10.78; S,8.22;Cl,9.09. Found: C,49.17; H,6.22; N,10.77; S,8.28; Cl,9.26.

EXAMPLE 2

To a mixture ofN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-aminobenzamide (700 mg),triethylamine (1.02 g), and methylene chloride (14 ml), methanesulfonylchloride (870 mg) is added dropwise with stirring at room temperature,and the resultant mixture is stirred at room temperature for 1 hour. Thereaction mixture is mixed with water, made alkaline with aqueous sodiumhydrogencarbonate, and shaken with methylene chloride. The organic layeris washed with water, dried over sodium sulfate, and evaporated toremove the methylene chloride. The residue is chromatographed on acolumn of alumina, which is eluted with methylene chloride. Afterevaporating the solvent from eluate, the residue is recrystallized fromethyl acetate/isopropyl ether to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-N,N-bis(methanesulfonyl)aminobenzamide(582 mg). The product is recrystallized from ethyl acetate to givecrystals melting at 160° to 161° C.

Anal. Calcd. for C₁₇ H₂₇ O₆ N₃ S₂ : C,47.0; H,6.28; N,9.69; S,14.79.Found: C,47.25; H,6.30; N,9.55; S,14.99.

Then, as an eluent is used 3% methanol/methylene chloride, wherebyN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-methanesulfonamidobenzamideis obtained. The eluate is evaporated, and the residue is crystallizedfrom ethyl acetate/isopropyl ether to give the product (148 mg), whichis recrystallized from ethyl acetate to give crystals melting at 170° to171.5° C.

Anal. Calcd. for C₁₆ H₂₅ O₄ N₃ S: C,54.06; H,7.09; N,11.82; S,9.02.Found C,54.35; H,7.18; N,11.74; S,9.29.

(2) A suspension ofN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-N,N-bis(methanesulfonyl)aminobenzamide(290 mg) in 10% sodium hydroxide (2.9 ml) and methanol (2.9 ml) iswarmed for 5 minutes on a water bath, whereby a clear solution isobtained. After evaporating the solvent, the residue is mixed with icywater, acidified with 6 N hydrochloric acid, made weakly alkaline withaqueous sodium hydrogencarbonate, and shaken with methylene chloride.The organic layer is washed with water, dried over sodium sulfate, andevaporated to remove the solvent. The residue is washed with ethylacetate/isopropyl ether to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-methanesulfonamidobenzamide(148 mg), which is recrystallized from ethyl acetate/isopropyl ether togive crystals melting at 170° to 171.5° C.

EXAMPLE 3

(1) To a mixture ofN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-aminobenzamide (700 mg),methylene chloride (14 ml), and triethylamine (1.03 g), benzenesulfonylchloride (1.35 g) is added at room temperature, and the resultantmixture is allowed to stand at room temperature. The reaction mixture ismixed with water, made alkaline with aqueous sodium hydrogen-carbonate,and shaken with methylene chloride. The organic layer is washed withwater, dried over sodium sulfate, and evaporated to remove the solvent.The residue is dissolved in methylene chloride, and chromatographed on acolumn of alumina, which is eluted with methylene chloride. Afterevaporating the methylene chloride from the eluate, the residue isrecrystallized from ethyl acetate/isopropyl ether to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-N,N-bis(benzenesulfonyl)aminobenzamide(839 mg) as crystals melting at 166° to 170° C.

Anal. Calcd. for C₂₇ H₃₁ O₆ N₃ S₂.1/2H₂ O: C,57.23; H,5.69; N,7.42;S,11.32. Found: C,57.26; H,5.69; N,7.20; S,11.50.

(2) A mixture of above product (500 mg), 10% sodium hydroxide (7.5 ml),and methanol (7.5 ml) is warmed on a water bath for 5 minutes. Afterevaporating the methanol from the reaction mixture, the residue is mixedwith water, acidified with hydrochloric acid, made alkaline again withaqueous sodium hydrogencarbonate, and shaken with methylene chloride.The organic layer is dried and evaporated to remove the solvent. Theresidue is washed with ethyl acetate/isopropyl ether to giveN-(1-ethyl-2-pyrroidinylmethyl)-2-methoxy-5-benzenesulfonamidobenzamide(325 mg). This product is recrystallized from ethyl acetate to givecrystals melting at 177° to 178° C.

Anal. Calcd. for C₂₁ H₂₇ O₄ N₃ S: C,60.41; H,6.52; N,10.06; S,7.68.Found: C,60.40; H,6.52; N,9.95; S,7.74.

EXAMPLE 4

(1) A mixture ofN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-nitrobenzamide (1.5 g),platinum oxide (150 mg), and methnol (30 ml) is subjected to catalytichydrogenation by shaking under hydrogen stream. The reaction mixture isworked up in a conventional manner and evaporated to remove themethanol. The residue is mixed with sodium azide (500 mg), ethylorthoformate (5 ml), and acetic acid (5 ml), and the resultant mixtureis heated at 80° C. for 1 hour. The reaction mixture is mixed with icywater, made alkaline with sodium carbonate, and shaken with methylenechloride. The organic layer is washed with water, dried over sodiumsulfate, and evaporated to remove the solvent. The residue iscrystallized from ethyl acetate/isopropyl ether to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide(1.3 g) as crystals melting at 171° to 174° C.

Anal. Calcd. for C₆ H₂₂ O₂ N₆ : C,58.16; H,6.71; N,25.44. Found:C,57.87; H,6.71; N,25.36.

(2) A mixture of above prouct (1.3 g), ethanol (9.8 ml), water (3.3 ml),and 10% sodium hydroxide (6.5 ml) is heated at 80° C. for 40 minutes.After evaporating the ethanol, the residue is acidified with 6 Nhydrochloric acid, made alkaline with triethylamine, salted out withsodium chloride, and shaken with 5% methanol/methylene chloride. Theorganic layer is dried over sodium sulfate and evaporated to remove thesolvent. The residue is washed with ethyl acetate to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-cyanoaminobenzamide (641mg), which is recrystallized from ethyl acetate to give crystals meltingat 134° to 139° C.

Anal. Cald. for C₁₆ H₂₂ O₂ N₄ : C,63.55; H,7.30; N,18.53. Found:C,63.53; H,7.41; N,18.37.

(3) A solution of above product (300 mg) and pyridine (1.5 ml) is mixedwith methanesulfonyl chloride (340 mg) at room temperature, and theresultant mixture is stirred at room temperature for 2 hours, andstirred at 50° C. for 30 minutes. The reaction mixture is mixed withaqueous sodium carbonate and shaken with methylene chloride. The organiclayer is washed with water, dried over sodium sulfate, and evaporated toremove the solvent. The residue is dissolved in methylene chrloride andchromatographed on a column of alumina, which is eluted with methylenechloride. After evaporating the methylene chloride from the eluate, theresidue is washed with ether/isopropyl ether and recrystallized to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-(N-cyanomethanesulfonamido)benzamide(99 mg) as crystals melting at 50° to 54° C.

Anal. Calcd. for C₁₇ H₂₄ O₄ N₄ S: C,53.67; H,6.36; N,14.73; S,8.43.Found: C,53.27; H,6.39; N,14.40; S,8.35.

EXAMPLE 5

To a solution ofN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-ethanesulfonamidobenzamide(266 mg) in dry acetone (7 ml), potassium carbonate and dimethylsulfate(100 mg) are added, and the resultant mixture is refluxed for 30minutes. After evaporating the acetone, the residue is mixed with waterand shaken with methylene chloride. The organic layer is washed withwater, dried over sodium sulfate, and evaporated to remove the solvent.The residue is dissolved in methylene chloride, and the resultantmixture is chromatographed on a column of alumina, which is eluted withmethylene chloride. After evaporating the eluate to remove the methylenechloride, the residue is washed with isopropy ether and recrystallizedfrom ethyl acetate/isopropyl ether in that order to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-(N-methylethanesulfonamido)benzamide(74 mg) as crystals melting at 85° to 87° C.

Anal. Calcd. for C₁₈ H₂₉ O₄ N₃ S: C,56.37; H,7.62; N,10.96; S,8.36.Found: C,56.55; H,7.68; N,10.80; S,8.61.

EXAMPLES 6-23

Using the following starting materials (IV), the reactions are effectedas in Example 1, whereby the corresponding products (I) are obtained.

    ______________________________________                                         ##STR15##                                                                     ##STR16##                                                                           IV           I                                                         Ex. No   R.sup.2                                                                              R.sup.3   R.sup.4                                                                           R.sup.1 m.p. (°C.)                       ______________________________________                                         6       F      H         H   Me      128.5-130                                7       Cl     H         H   Et      138-139                                  8       Cl     H         H   Pr      131-132                                  9       Da     H         H   Me      119-120.5                               10       H      H         H   Et      156-157                                 11       H      H         H   Da      141-142                                 12       H      H         H   Bu      130-131.5*                              13       H      Met       H   Me      119-120                                 14       Met    H         H   Me      152-154                                 15       Me     H         H   Et      140-141                                 16       Me     H         H   Me      131-132                                 17       Et     H         H   Me      135-136                                 18       H      Me        H   Et      117-118                                 19       Et     H         H   Et      82-83.5                                 20       H      Me        H   Me      111.5-112.5                             21       Me     H         H   Da      129-129.5                               22       Cl     H         H   Me      146-146.5                               23       H      H         Cl  Me      97-97.5                                 ______________________________________                                         Note: The abbreviations have the following significance: Et (ethyl), Da       (dimethylamino), Bu (butyl), Me (methyl), Met (methoxy), F (fluorine), H      (hydrogen), Cl (chlorine)                                                     *Hydrochloride of this product shows a melting point of 202 to 203.degree     C. (decomp.)                                                             

EXAMPLE 24

To a solution ofN-(1-cyclohexyl-3-pyrrolidinyl)-2-methoxy-5-aminobenzamide (1.0 g) indry pyridine (5 ml), methanesulfonyl chloride (308 mg) is added with icecooling, and the reaction mixture is stirred at room temperature for 20minutes. The reaction mixture is worked up as in Example 1 to giveN-(1-cyclohexyl-3-pyrrolidinyl)-2-methoxy-5-methanesulfonamidobenzamide(731 mg) as crystals melting at 170° to 171.5° C.

Anal. Calcd. for C₁₉ H₂₉ O₄ N₃ S: C,57.70; H,7.39; N,10.62; S,8.11.Found: C,57.89; H,7.47; N,10.45; S,8.37.

EXAMPLE 25

(1) To a mixture of methyl 2-methoxy-5-aminobenzoate (300 mg), drymethylene chloride (6 ml), and triethylamine (368 mg), a solution ofmethanesulfonyl chloride (400 mg) in dry methylene chloride (1 ml) isadded dropwise with ice cooling, and the resultant mixture is stirred atroom temperature for 1 hour. The reaction mixture is made alkaline withaqueous sodium hydrogencarbonate and shaken with methylene chloride. Theorganic layer is washed with water, dried over sodium sulfate, andevaporated under reduced pressure to remove the methylene chloride. Theresidue is washed with ethyl acetate/isopropyl ether to give methyl2-methoxy-5-N,N-bis(methanesulfonyl)aminobenzoate (520 mg), which isrecrystallized to give crystals melting at 169° to 169.5° C.

Anal. Calcd. for C₁₁ H₁₅ O₇ NS₂ : C,39.16; H,4.48; N,4.15; S,19.01.Found: C,39.04; H,4.45, N,4.04; S,19.01.

(2) To a mixture of tetrahydrofuran (3 ml) and 10% aqueous sodiumhydroxide (3 ml), above product (300 mg) is added, and the resultantmixture is stirred with heating at 50° C. for 1.25 hours. Afterevaporating the reaction mixture under reduced pressure to remove thesolvent, the residue is acidified with 6 N hydrochloric acid, salted outwith sodium chloride, and shaken with methylene chloride containing asmall amount of methanol. The organic layer is washed with saturatedbrine, dried over sodium sulfate, and evaporated under reduced pressureto remove the solvent. The residue is washed with isopropyl ether togive 2-methoxy-5-methanesulfonamidobenzoic acid (175 mg) as crystalsmelting at 166° to 167.5° C.

(3) A mixture of above product (150 mg) and thionyl chloride (3 ml) isrefluxed with heating for 30 minutes. After evaporating the reactionmixture under reduced pressure to remove the thionyl chloride, theresidue is mixed with dry benzene and evaporated again under reducedpressure to remove the solvent. The residue is dissolved in drymethylene chloride (3 ml). To this solution, triethylamine (124 mg) anda solution of 1-ethyl-2-aminomethylpyrrolidine (90 mg) in dry methylenechloride (1 ml) is dropwise in that order added with ice cooling, andthe resultant mixture is stirred at room temperature for 15 minutes. Thereaction mixture is made alkaline with aqueous sodium hydrogencarbonate,salted out with sodium chloride, and shaken with methylene chloride. Theorganic layer is washed with saturated brine, dried over sodium sulfate,and evaporated under reduced pressure to remove the methylene chloride.The residue is chromatographed on a column of alumina, which is elutedwith 1% methanol/methylene chloride-2% methanol/methylene chloride.After evaporating the eluate to remove the solvent, the residue isrecrystallized from ethyl acetate/isopropyl ether to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-methanesulfonamidobenzamide(143 mg). The product is recrystallized from ethyl acetate/isopropylether to give crystals melting at 171° to 172° C.

EXAMPLE 26

(1) To a solution of methyl 2-methoxy-5-aminobenzoate (300 mg) and drypyridine (3 ml), methanesulfonyl chloride (210 mg) is added dropwisewith ice cooling and stirring, and the resultant mixture is stirred atroom temperature for 1 hour. The reaction mixture is acidified with 6 Nhydrochloric acid and shaken with methylene chloride. The organic layeris washed with water, dried over sodium sulfate, and evaporated underreduced pressure to remove the methylene chloride. The residue ischromatographed on a column of silica gel, which is eluted withmethylene chloride-2% methanol/methylene chloride, and the eluate isevaporated to remove the solvent. The residue is recrystallized fromethyl acetate/isopropyl ether to give methyl2-methoxy-5-methanesulfonamidobenzoate (381 mg) as colorless prismsmelting at 84° to 86° C.

Anal. Calcd. for C₁₀ H₁₃ O₅ NS.1/10H₂ O: C,46.32; H,5.05; N,5.40;S,12.37. Found: C,45.77; H,5.14; N,5.30; S,12.32.

(2) A solution of above product (330 mg),1-ethyl-2-aminomethylpyrrolidine (245 mg) and n-propanol (7 ml) isrefluxed for 23 hours with heating. After cooling, the reaction mixtureis evaporated under reduced pressure to remove the n-propanol and theresidue is dissolved in dilute hydrochloric acid. The acidic solution isshaken with methylene chloride to remove the unreacted ester. Thehydrochloric acid layer is made alkaline with sodium hydrogencarbonate,salted out with sodium chloride, and shaken with methylene chloride. Theorganic layer is washed with saturated brine, dried over sodium sulfate,and evaporated under reduced pressure to remove the methylene chloride.The residue is chromatographed on a column of alumina, which is elutedwith 2% methanol/methylene chloride. The eluate is evaporated to removethe solvent. The residue is recrystallized from ethyl acetate/isopropylether to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-methanesulfonamidobenzamide(143 mg) as colorless scales melting at 171° to 172° C.

EXAMPLE 27

UsingN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-methanesulfonamidobenzamideand dimethyl sulfate, the reaction is effected as in Example 5, wherebyN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-(N-methylmethanesulfonamido)benzamideis obtained as crystals melting at 140.5° to 142° C.

EXAMPLE 28

(1) To a mixture ofN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-aminobenzamide(1.0 g), dry methylene chloride (20 ml), and triethylamine (693 mg) isadded dropwise a mixture of t-butylaminosulfonyl chloride (707 mg) andmethylene chloride (5 ml) with ice cooling and stirring. After stirringfor 15 minutes, the reaction mixture is mixed with aqueous sodiumhydrogencarbonate and shaken with methylene chloride. The organic layeris washed with water, dried over sodium sulfate, and evaporated toremove the solvent. The residue is chromatographed on a column ofalumina and eluted with 0-2% methanol/methylene chloride. The eluate isrecrystallized from ethyl acetate/isopropyl ether to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-t-butylaminosulfonamidobenzamide(1.0 g) as crystals melting at 167° to 168° C.

Anal. Calcd. for C₂₀ H₃₄ O₄ N₄ S: C,56.31; H,8.03; N,13.13; S,7.52.Found: C,56.23; H,8.11; N,12.84; S,7.70.

(2) Above product (700 mg) is mixed with trifluoroacetic acid (7 ml),stirred at room temperature for 3 hours, and evaporated to remove thetrifluoroacetic acid. The residue is mixed with aqueous ammonia, saltedout with saturated brine, and shaken with chloroform. The organic layeris washed with saturated brine, dried over sodium sulfate, andrecrystallized from ethyl acetate/ether to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-aminosulfonamidobenzamide(408 mg) as crystals melting at 140° to 141° C.

Anal. Calcd. for C₁₆ H₂₀ O₄ N₄ S: C,51.87; H,7.07; N,15.12; S,8.65.Found: C,51.87; H,7.07; N,14.81; S,8.63.

EXAMPLE 29-32

Using the following starting materials (IV), the reactions are effectedas in Example 28, whereby the corresponding products (I) and (Ib) areobtained.

    ______________________________________                                         ##STR17##                                                                     ##STR18##                                                                     ##STR19##                                                                    EX.     IV      I                Ib                                           No.     R.sup.2 R.sup.1    m.p. (°C.)                                                                      m.p. (°C.)                         ______________________________________                                        29      Cl      NH(t-Bu)   141-142 158-159                                    30      Cl      piperidino 139-141 --                                         31      Me      NHMe       157-158 --                                         32      H       NH(t-Bu)   --      140-141                                    ______________________________________                                         Note: The abbreviation has the following significance: t (tertiary)      

EXAMPLE 33

(1) A mixture of 2-methoxy-4-methyl-5-methanesulfonamidobenzoic acid (20g) and thionyl chloride (20 ml) is refluxed for 2.5 hours, and thereaction mixture is evaporated under reduced pressure to remove thethionyl chloride. The residue is mixed with dry benzene (10 ml) andtriethylamine (1.5 g), then a mixture of tetrahydrofurfurylamine (870mg) and dry benzene (2 ml) is added with ice cooling and stirring, andthe resultant mixture is stirred at room temperature for 15 minutes. Thereaction mixture is made alkaline with sodium hydrogencarbonate andshaken with methylene chloride. The organic layer is washed with water,dried over sodium sulfate, and evaporated to remove the methylenechloride. The residue is washed with ethyl acetate/isopropyl ether togiveN-tetrahydrofurfuryl-2-methoxy-4-methyl-5-methanesulfonamidobenzamide(2.21 g) as crystals melting at 207° to 208.5° C.

(2) A mixture of above product (1.5 g), thionyl chloride (9 ml), andchloroform (30 ml) is refluxed for 4 hours. The reaction mixture ispoured into icy water and shaken with methylene chloride, and theorganic layer is washed with aqueous sodium hydrogencarbonate and waterin that order and dried over sodium sulfate and evaporate. The residueis dissolved in methylene chloride and chromatographed on a column ofsilica gel, which is eluted with 1% methanol/methylene chloride. Afterremoving the solvent from the eluate, the residue is washed with ethylacetate/ether to giveN-(2,5-dichloropentyl)-2-methoxy-4-methyl-5-methanesulfonamidobenzamide(1.30 g) as crystals melting at 132° to 132.5° C.

(3) A solution of above product (100 mg) and 70% aqueous ethylamine iswarmed to 60° C. for 2.5 hours. The reaction mixture is cooled with ice,mixed with aqueous sodium hydrogencarbonate, salted out with sodiumchloride, and shaken with methylene chloride. The organic layer iswashed with saturated brine, dried over sodium sulfate, and evaporatedto remove the solvent. The residue is chromatographed on a column ofalumina and eluted with 1% methanol/methylene chloride. Afterevaporating the eluate to remove the solvent, the residue is washed withethyl acetate/isopropyl ether to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-methanesulfonamidobenzamide(42 mg) as crystals melting at 131.5° to 133° C.

EXAMPLE 34

(1) Using 2-methoxy-4-chloro-5-nitrobenzoic acid, the reaction iseffected as in Example 33 (1), wherebyN-tetrahydrofurfuryl-2-methoxy-4-chloro-5-nitrobenzamide (3.85 g) isobtained as crystals melting at 164° to 165° C.

A solution of above product (3.65 g), conc. hydrochloric acid (36.5 ml),water (18 ml), tetrahydrofuran (36.5 ml), and tin chips (4.13 g) isheated at 50° C. for 2 hours. The reaction mixture is evaporated toremove the solvent. The residue is mixed with icy water, made stronglyalkaline with sodium hydroxide, and shaken with methylene chloride. Theorganic layer is filtered to remove the insoluble part, washed withwater, dried over sodium sulfate, evaporated to remove the solvent, andrecrystallized from ethyl acetate/ether to giveN-tetrahydrofurfuryl-2-methoxy-4-chloro-5-aminobenzamide as crystalsmelting at 109° to 110° C.

Above product (3.6 g) is dissolved in methylene chloride (36 ml) andtriethylamine (2.85 g), then mixed with methanesulfonyl chloride (3.08g) and methylene chloride (7.2 ml) with ice cooling and the resultantmixture is heated around the boiling point of the solvent for 30 minuteswith stirring. The reaction mixture is shaken with aqueous sodiumhydrogen-carbonate. The methylene chloride layer is washed with water,dried over sodium sulfate, and evaporated to remove the solvent. Theresidue is mixed with 10% aqueous sodium hydroxide (61 ml) andtetrahydrofuran (10 ml) and stirred at 50° C. for 1.25 hour. Theresultant mixture is acidified with conc. hydrochloric acid, shaken withmethylene chloride, washed with water, dried over sodium sulfate, andevaporated to remove the solvent. The residue is washed with ethylacetate/ether and recrystallized from methylene chloride/ethyl acetateto giveN-tetrahydrofurfuryl-2-methoxy-4-chloro-5-methanesulfonamidobenzamide(2.82 g) as crystals melting at 159° to 160° C.

(2) Using the above product, the reaction is effected as in Example 33(2), wherebyN-(2,5-dichloropentyl)-2-methoxy-4-chloro-5-sulfonamidobenzamide isobtained as crystals melting at 105° to 106.5° C.

(3) Using above product (1.3 g) and 70% aqueous ethylamine (26 ml), thereaction is effected as in Example 33 (3), wherebyN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-methanesulfonamidobenzamide(452 mg) is obtained as crystals melting at 126° to 127.5° C.

EXAMPLE 35

(1) To a solution of 2-methoxy-4-methyl-5-nitrobenzoyl chloride (7.0 g),methylene chloride (35 ml) and triethylamine (7.68 g) is added a mixtureof tetrahydrofurfurylamine (4.33 g) and dry benzene (11 ml) with icecooling and stirring. The resultant mixture is allowed to stand at roomtemperature for 20 minutes, mixed with water and shaken with methylenechloride. The organic layer is dried over sodium sulfate and evaporatedto remove the solvent. The residue is washed with ethylacetate/isopropyl ether and recrystallized from methylene chloride/ethylacetate to give N-tetrahydrofurfuryl-2-methoxy-4-methyl-5-nitrobenzamide(7.1 g) as crystals melting at 178° to 179.5° C.

Above product (8.1 g) is reduced in a conventional manner using platinumoxide (810 mg) and methanol (162 ml) to giveN-tetrahydrofurfuryl-2-methoxy-4-methyl-5-aminobenzamide (7.81 g) as anoil.

A mixture of above product (500 mg), dimethylsulfamoyl chloride (543mg), triethylamine (382 mg), and dry benzene (10 ml) is refluxed for 18hours. The reaction mixture is evaporated to remove the solvent, madealkaline with 10% aqueous sodium hydroxide, and shaken with ether. Thealkaline solution is acidified with 6 N hydrochloric acid and shakenwith methylene chloride. The organic layer is dried over sodium sulfateand evaporated to remove the solvent to give a gelatinous product, whichis chromatographed on a column of silica gel and eluted with 2%methanol/methylene chloride. The eluate is evaporated to remove thesolvent, and the residue is washed with ethyl acetate/isopropyl ether togiveN-tetrahydrofurfuryl-2-methoxy-4-methyl-5-dimethylaminosulfonamidobenzamide(315 mg) as crystals melting at 130° to 131° C.

(2) Using above product (700 mg), thionyl chloride (4.2 ml), andchloroform (14 ml), the reaction is effected as in Example 33 (2),wherebyN-(2,5-dichloropentyl)-2-methoxy-4-methyl-5-dimethylaminosulfonamidobenzamide(618 mg) is obtained as an oil.

(3) Using above product and 70% aqueous ethylamine (3.1 ml), thereaction is effected as in Example 33 (3), wherebyN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-dimethylaminosulfonamidobenzamide(305 mg) is obtained as crystals melting at 126° to 128° C.

EXAMPLES 36-39

Using the following starting materials (II) and the amine (III) thereactions are effected as in Example 33 (3), whereby the correspondingproducts(I) are obtained.

    ______________________________________                                         ##STR20##                                                                     ##STR21##                                                                    Ex.       I                                                                   No.       R.sup.2  R.sup.5       m.p. (°C.)                            ______________________________________                                        36        Me       allyl         141.5-143                                    37        Me       benzyl        125-129                                      38        Cl       allyl         118-118.5                                    39        Cl       p-fluorobenzyl                                                                              138-142                                      ______________________________________                                    

EXAMPLE 40

A mixture ofN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-methanesulfonamidobenzamide(500 mg), triethylamine (823 mg), dimethylaminosulfonyl chloride (1.17g), and methylene chloride (20 ml) is refluxed for 39 hours. Thereaction mixture is washed with aqueous sodium hydrogen-carbonate. Theorganic layer is washed with water, dried over sodium sulfate, andevaporated to remove the solvent. The residue is chromatographed on acolumn of alumina and eluted with 0.5-1% methanol/methylene chloride.The eluate is evaporated to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-[N-(dimethylaminosulfonyl)methanesulfonamido]benzamide(351 mg) as an oil. This product is mixed with tetrahydrofuran (3 ml)and 10% sodium hydroxide (3 ml) and warmed at 80° C. for 1 hour. Thereaction mixture is evaporated to remove the tetrahydrofuran, acidifiedwith hydrochloric acid, made alkaline with sodium hydrogen-carbonate,salted out with sodium chloride, and shaken with methylene chloride. Theorganic layer is washed with saturated brine, dried over sodium sulfate,and evaporated to remove the solvent. The residue is chromatographed ona column of alumina and eluted with 3% methanol/methylene chloride. Theeluate is evaporated to remove the solvent. The residue is washed withether/isopropyl ether and filtered to giveN-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-dimethylaminosulfonamidobenzamide(211 mg). The product is recrystallized from acetonitrile/isopropylether to give crystals melting at 129° to 129.5° C.

EXAMPLE 41

    ______________________________________                                        N--(1-Ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-                                                     100 g                                             5-dimethylaminosulfonamidobenzamide                                           Lactose                     192 g                                             Wheat starch                 96 g                                             Carboxymethyl cellulose sodium                                                                             10 g                                             Magnesium stearate           2 g                                              ______________________________________                                    

These ingredients are admixed, kneaded with water, and granulated with agranulator in a conventional manner. The resulting granules are sievedthrough a 20 mesh sieve and made into 2000 tablets each containing 50 mgof the effective ingredient and weighing 200 mg. The tablets are coatedwith syrup to give sugar coated tablets.

What we claim is:
 1. A method of treating a patient suffering from apsychotic disorder, which comprises administering to the patient apharmaceutically effective amount of a compound selected from the groupconsisting of a compound of the formula ##STR22## wherein R is hydrogenor methyl, R¹ is methyl, ethyl or dimethylamino, R² is hydrogen,chlorine, fluorine, methyl or methoxy, and R⁵ is methyl, ethyl or vinyl,and a pharmaceutically acceptable acid addition salt thereof.
 2. Apharmaceutical composition which can be used as a psychotropic agent,comprising a pharmaceutically effective amount of a compound selectedfrom the group consisting of a compound of the formula ##STR23## whereinR is hydrogen or methyl, R¹ is methyl, ethyl or dimethylamino, R² ishydrogen, chlorine, fluorine, methyl or methoxy, and R⁵ is methyl, ethylor vinyl, and a pharmaceutically acceptable acid addition salt thereof,anda pharmaceutically acceptable carrier therefor.